ABSTRACT Lysophosphatidic acid (LPA) signaling has the potential to be of therapeutic value in periodontal disease (PD). LPA is central to homeostasis and pathophysiology, existing in bodily fluids at low levels in health, and becoming elevated in inflammation and pathology. Key to periodontal disease (PD), LPA is essential to all aspects of bone biology and inflammation (Jesionowska et al., 2014). The secreted enzyme autotaxin (ATX) makes the majority of LPA and is found elevated in inflammatory pathophysiologies in other systems. In PD, over-activation of inflammatory pathways leads to immune-mediated periodontal tissue and bone damage and destruction. Therefore, LPA and ATX are likely to contribute significantly to the pathogenesis of PD. Our central hypothesis is that LPA controls the expression of key inflammatory mediators that contribute to the periodontal tissue destruction and bone loss. However, it is not known how LPA contributes to the hallmark of PD, inflammation. Therefore, this proposal addresses the urgent need to correct this knowledge gap in order to be able to pharmacologically modulate this central inflammatory mediator?s signaling system in PD. Our in vitro studies with primary human gingival (GF) and periodontal ligament (PDLF) fibroblasts confirmed that they express the LPA receptor (LPAR) subtypes LPA1-5 at high levels (Cerutis et al. 2010) and that LPA positively regulates their in vitro wound-healing and regenerative responses (George et al., 2009) by signaling mainly through LPA1 and LPA3. We also found elevated LPA levels (?M) in PD patient saliva and gingival crevicular fluid (GCF) (Bathena et al. 2011), and that LPA profoundly regulates transcription of > 60 key inflammation- related GF cytokines, their receptors, enzymes, and other mediators (Cerutis et al. 2015a) further supporting our central hypothesis. Therefore, the rationale for this proposed research is that individual LPA subtypes may be innovatively manipulated pharmacologically to treat PD by favoring oral healing. We will test our central hypothesis using a mouse model of P. gingivalis- induced PD to answer several fundamental questions via three specific aims: Aim 1. Determine if an LPA1 antagonist can prevent or reduce PD-induced periodontal tissue and alveolar bone loss. Aim 2. Determine if an ATX inhibitor can prevent or reduce PD-induced periodontal tissue and alveolar bone loss. Aim 3. Identify in vitro if the production of key PD inflammatory molecules can be diminished via administration of LPA1 and/or LPA3 antagonists. We expect these studies to provide a strong seminal foundation for defining the role of LPA in PD, and to identify the edg family LPAR subtype(s) most associated with PD development and periodontal tissue and bone destruction. These studies will advance the field of Periodontology by identifying the basic actions of LPA, a lipid mediator heretofore unrecognized to contribute to PD pathogenesis. Expected results: the contribution of LPA and its receptors interacting with known PD-regulatory cytokine networks will be able to be targeted and manipulated in new ways to treat PD, which worsens many common health conditions like cardiovascular disease and diabetes.